Atherosclerotic vascular disease remains the leading cause of death in the United States with the majority of mortality due to coronary artery disease and myocardial infarction. Risk factor modification such as reductions in hyperlipidemia constitutes the only treatment strategy available for this vexing disease. Thus, there is an active effort to identify the culprit cellular processes that provide mechanistic insight. Recent reports f the proatherogenic phenotype of mice with a macrophage-specific autophagy deficiency has renewed interest in the role of the autophagy-lysosomal system in atherosclerosis. Lysosomes have the unique role of processing both exogenous material such as excess atherogenic lipids and endogenous cargo that includes dysfunctional proteins and organelles. Since little is known about the effect of an atherogenic environment on macrophage lysosomes, we aimed to test the notion that lysosomal dysfunction is the product of lipid metabolism and evaluate novel ways to ameliorate this effect. Our preliminary data demonstrate that macrophages develop features of lysosome dysfunction upon exposure to atherogenic lipids. In turn, this lysosomal stress can activate TFEB, the only known transcription factor that can broadly stimulate lysosomal biogenesis and function. The regulation of macrophage TFEB appears to be critically linked to mTOR signaling, buttressed by the observation that the classic mTOR inhibitor Rapamycin can induce lysosomal biogenesis while reducing macrophage dysfunction and atherosclerosis. Understanding the links between lipid metabolism and lysosomal biogenesis has important implications in understanding plaque progression. We propose to test the hypothesis that macrophage lysosomal biogenesis mediated by the transcription factor TFEB is an important compensatory response during atherosclerosis and serves an atheroprotective role. A variety of mouse models capable of dissecting the role of TFEB action in macrophages will serve as the research tools to address this hypothesis both in vitro and in vivo.